Mitogen-activated protein kinase-activated protein kinases 2 and 3 regulate SERCA2a expression and fiber type composition to modulate skeletal muscle and cardiomyocyte function.
Mitogen-activated protein kinase-activated protein kinases 2 and 3 regulate SERCA2a expression and fiber type composition to modulate skeletal muscle and cardiomyocyte function.
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丝裂原激活蛋白激酶激活蛋白激酶 2 和 3 调节 SERCA2a 表达和纤维类型组成，以调节骨骼肌和心肌细胞功能。
DOI：
10.1128/mcb.01692-12
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发表时间：
2013
影响因子：
5.3
通讯作者：
Scharf M
中科院分区：
文献类型：
--
作者：
Scharf M
丝裂原活化蛋白激酶（MAPK）活化蛋白激酶2和3（MK 2/3）代表p38 MAPK下游的蛋白激酶。使用MK2/3双敲除（MK2/3−/−）小鼠，我们通过转录组和蛋白质组分析以及组织学分析了MK2/3在横纹肌中的作用。我们证明了缓慢氧化骨骼肌肌纤维基因程序的表达增强，包括过氧化物酶体增殖物激活受体γ（PPARγ）辅激活因子1α（PGC-1α）。使用报告基因和电泳凝胶迁移率变动分析，我们证明，MK 2催化活性直接调节快纤维特异性肌球蛋白重链IId/x和慢纤维特异性肌/内质网Ca 2 +-ATP酶2（SERCA 2）基因的启动子。由转录因子Egr-1与Sp1的比率降低引起的SERCA 2a基因表达升高与MK2/3−/−心肌细胞的加速松弛和增强收缩性相关，同时改善MK2/3−/−比目鱼肌的力参数。这些结果将MK2/3与钙动力学的调节联系起来，并通过在MK2/3−/−小鼠中产生表现出降低的疲劳性和增强的力量的独特肌肉表型，将MK2/3的酶活性确定为调节横纹肌功能的关键因素。因此，p38-MK2/3轴可能是设计与纤维类型变化或SERCA 2功能受损相关疾病的治疗策略的新靶点。
The mitogen-activated protein kinase (MAPK)-activated protein kinases 2 and 3 (MK2/3) represent protein kinases downstream of the p38 MAPK. Using MK2/3 double-knockout (MK2/3−/−) mice, we analyzed the role of MK2/3 in cross-striated muscle by transcriptome and proteome analyses and by histology. We demonstrated enhanced expression of the slow oxidative skeletal muscle myofiber gene program, including the peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α). Using reporter gene and electrophoretic gel mobility shift assays, we demonstrated that MK2 catalytic activity directly regulated the promoters of the fast fiber-specific myosin heavy-chain IId/x and the slow fiber-specific sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) gene. Elevated SERCA2a gene expression caused by a decreased ratio of transcription factor Egr-1 to Sp1 was associated with accelerated relaxation and enhanced contractility in MK2/3−/−cardiomyocytes, concomitant with improved force parameters in MK2/3−/−soleus muscle. These results link MK2/3 to the regulation of calcium dynamics and identify enzymatic activity of MK2/3 as a critical factor for modulating cross-striated muscle function by generating a unique muscle phenotype exhibiting both reduced fatigability and enhanced force in MK2/3−/−mice. Hence, the p38-MK2/3 axis may represent a novel target for the design of therapeutic strategies for diseases related to fiber type changes or impaired SERCA2 function.